PDF(Pubmed)
Abstract：
Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9-12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9-12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT-qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9-12 alleles using nanopore long-sequencing. Using the Kruskal-Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9-12 and identifying which of them has developed cancer.
摘要：
遗传性乳腺癌和卵巢癌（HBOC）综合征是一种遗传性疾病，使乳腺癌的风险增加80％，卵巢癌的风险增加40％。引起HBOC的最常见致病变异（PVs）发生在BRCA1基因中，有超过3850个报道的基因突变序列。由于创始人突变的影响，BRCA1中特定PV的患病率在人群中有所增加。因此,当发现创始人突变时，它成为改善癌症风险表征和有效筛查方案的关键。墨西哥人群中描述的唯一的创始人突变是BRCA1外显子9至12的缺失（BRCA1Δ9-12），它的描述集中在基因序列上，但是没有为携带该基因的个体生成转录谱。在这项研究中,我们描述了癌症患者和健康个体的转录谱谁是杂合的PVBRCA1Δ9-12通过分析两个等位基因的差异表达与纯合BRCA1对照组使用RT-qPCR相比，我们使用纳米孔长测序描述了BRCA1野生型和BRCA1Δ9-12等位基因产生的同工型。使用Kruskal-Wallis测试,我们的结果显示健康杂合组和纯合BRCA1对照组之间野生型等位基因的转录表达相似.还观察到HBOC患者中两种等位基因的复发和表达增加之间的关联。对序列的分析表明，四种野生型同工型具有诊断潜力，可用于辨别携带PVBRCA1Δ9-12的个体并鉴定其中哪些已发展为癌症。
